The objective is to develop an understanding of the pathophysiologic mechanisms of aminoglycoside antibiotic toxicity at a biochemical level, to concurrently develop a safe and sensitive human model for the efficient assessment of aminoglycoside effects, and to utilize this clinical model for the application of results of the basic studies to the investigation of safer aminoglycoside antibiotics and safer modes of administration of existing aminoglycoside antibiotics. The basic pathophysiologic mechanisms of aminoglycoside nephrotoxicity will be investigated in terms of the mechanism of renal transport of aminoglycosides and the biochemical effects of accumulated aminoglycosides in the kidney with emphasis on our preliminary findings of inhibition of a renal sodium-potassium ATP' ase by aminoglycosides. The mechanism of this ATP' ase inhibition by aminoglycosides will be explored from a biochemical standpoint and also in an attempt to verify or negate the pathophysiologic consequences of such an effect. The development of a safe and sensitive human model for aminoglycoside effects on the kidney will emphasize the sensitive measurement of renal tubular and glomerular function in humans receiving a dosage regimen that is safe and with which the investigators have had considerable experience. Our belief is that with such a model it should be possible to study various new aminoglycosides and various modes of administration of existing amino-glycosides with far greater efficiency than can now be done in large-scale clinical trials.